Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Li Q, Bohin N, Wen T, Ng V, Magee J, Chen SC, et al. Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 2013; 504:143–7.Li and colleagues tested how mutational activation of NRASG12D, a mutation found in human leukemia that, in mice, leads to myeloproliferative neoplasms, affected proliferation and self-renewal programs. Targeting NrasG12D to the hematopoietic stem cell (HSC) compartment and using specific marker and label retention assays, they found that despite NrasG12D, preleukemic HSCs still showed normal features: a slow-cycling population with high self-renewal and a faster dividing subpopulation with reduced self-renewal. Although increased HSC proliferation was not followed by increased total cell numbers, the authors detected an expansion of the primitive hematopoietic progenitors that eventually gave rise to different lineages. The NrasG12D clone outcompeted the wild-type HSCs up to four generations. These results show that NrasG12D mutations create a clonal population that retains some control from the natural bone marrow microenvironment, yet still outcompetes normal HSCs and becomes dominant. This insightful work provides evidence on how a preleukemic clone may persist for long periods and be prone to accumulating further mutations that could lead to full malignancy.Cruickshanks HA, McBryan T, Nelson DM, Vanderkraats ND, Shah PP, van Tuyn J, et al. Senescent cells harbour features of the cancer epigenome. Nat Cell Biol 2013; 15:1495–506.Cellular senescence is an important mechanism of tumor suppression, and escape from senescence is a critical step in tumorigenesis. Cruickshanks and colleagues compare methylation patterns of replicative senescent and proliferating cells by whole-genome bisulfite sequencing. They identify an overall pattern of DNA hypomethylation—possibly due to failed maintenance of methylation, and focal DNA hypermethylation in senescent cells. Comparing differentially methylated regions between proliferating, senescent, and cancer cells (breast and colon), they identify similar methylation patterns between senescent and cancer cells. Furthermore, by comparing the methylation pattern in cells before and after bypass of senescence, the authors suggest that alterations in methylation precede escape from senescence and persist during malignant progression. Due to the profound role for DNA methylation in diverse cellular processes, the authors suggest that epigenomic alterations present in senescent cells may actually promote tumorigenesis after escape from senescence. In addition, the accumulation of senescent cells over time may contribute to the increased incidence of cancer with aging. Although additional data are required, these findings suggest that multiple determinants of DNA methylation patterns may exist in cancer.Salt MB, Bandyopadhyay S, McCormick F. Epithelial to mesenchymal transition rewires the molecular path to PI3-kinase-dependent proliferation. Cancer Discovery; Published OnlineFirst December 3, 2013; doi:10.1158/2159-8290.CD-13-0520.Epithelial-to-mesenchymal transition (EMT), a component of normal development, is reactivated in some human tumors. Salt and colleagues found that induction of EMT resulted in loss of activated ERBB3 and AKT, and of activated AKT targets PRAS40 (AKT1S1) and p70S6K (RPS6KB2). Growth was markedly reduced in the mesenchymal state and was rescued upon transfection of PI3Kα. By immunoprecipitation, they showed that ERBB3 was associated with p85, the regulatory PI3K subunit, and also that autocrine stimulation by the ERBB3 ligand neuregulin was responsible for PI3K activation in the epithelial state. They confirmed the central role of ERBB3 in regulation of proliferation as a function of EMT by showing that restored expression of ERBB3 rescued mesenchymal-differentiated cell proliferation and AKT activation. To evaluate the role of EMT in sensitivity to small molecular pathway inhibitors, the authors determined that EMT did not affect response to PI3K inhibition. EMT did reduce the sensitivity to EGFR inhibition and was mimicked by ERBB3 knockdown, with resistance to EGFR inhibition correlating with EMT score. Finally, human mesenchymal lung tumors had loss of ERBB3 and positive correlations of ERBB3 and E-cadherin expression, but PI3K activation was maintained in mesenchymal tumors. With this work, Salt and colleagues have described a mechanism through which EMT alters the proliferative potential of cancer cells via ERBB3.Cho J, Chen L, Sangji N, Okabe T, Yonesaka K, Francis JM, et al. Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res 2013;73:6770–9.Activating kinase domain mutations of EGFR occur in lung adenocarcinoma and are associated with responses to EGFR inhibitors. Cetuximab is a chimeric monoclonal antibody that binds to EGFR and can block ligand-induced dimerization. Introducing dimerization-impairing mutations into NIH3T3 cells expressing lung cancer derived Ex19Del, Ex20Ins, and T790M EGFR mutants, Cho and colleagues observed no change in colony formation, suggesting that these mutants could induce transformation without dimerization, in contrast with findings from the same experiment performed in cells with L858R EGFR mutations, where colony-forming activity was significantly reduced in response to blocking dimerization. Flow cytometry revealed comparable EGFR protein expression in dimerization-competent versus dimerization-impaired mutant cells. Dimerization-independent activation has not been previously reported, and the investigators further assessed the ability of EGFR mutants to be activated biochemically without dimerization. Ex19Del and Ex20ns mutants were active in either the receiver or the activator conformation, which explains their ability to induce cellular transformation in the absence of dimerization, unlike the L858R mutant and wild-type EGFR, which were only active in the dimerization-activated receiver conformation. Given that inhibition of dimerization is one proposed mechanism of action for cetuximab, the investigators further explored the potency of this antibody against distinct EGFR mutants and found that the dimerization-dependent L858R mutant was cetuximab sensitive whereas the dimerization-independent Ex19Del, Ex20Ins, and T790M mutants were not. They expanded these studies to lung cancer-derived cell lines and transgenic mouse models, which revealed similar differential efficacy. Interestingly, cetuximab could still block phosphorylation of dimerization-independent EGFR mutants. Nevertheless, these mutants remained active and were resistant to cetuximab.Murphy BL, Obad S, Bihannic L, Ayrault O, Zindy F, Kauppinen S, et al. Silencing of the miR-17∼92 cluster family inhibits medulloblastoma progression. Cancer Res 2013; 73:7068–78.Medulloblastoma is the most common malignant brain tumor in children. A third of these tumors show activation of Sonic Hedgehog (SHH) signaling and increased expression of microRNAs (miRNA) encoded by the miR-17∼92 and miR-106b∼25 clusters. Locked nucleic acid (LNA) modified anti-miRNA oligonucleotides were generated that inhibited miRNA seed families expressed by miR-17∼92 and miR-106b∼25. Medulloblastoma cells took up the tiny 8-mer LNAs, which specifically inhibited the targeted miRNA seed-sharing family members. In in vitro studies, and in two mouse models for SHH-driven medulloblastoma, Murphy and colleagues found that anti-miRNA–driven inhibition of miR-17 and miR-19a families resulted in decreased tumor cell proliferation and tumor growth and extended survival. These results suggest the therapeutic potential of LNAs targeting the miR-17∼92 cluster in treatment of SHH medulloblastomas.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.